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J. Biol. Chem., Vol. 282, Issue 47, 34457-34467, November 23, 2007

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A Novel Interaction between Procaspase 8 and SPARC Enhances Apoptosis and Potentiates Chemotherapy Sensitivity in Colorectal Cancers^*

From the Division of Gastroenterology, University of British Columbia, and Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1M9, Canada

Chemotherapy resistance accounts for the high mortality rates in patients with advanced cancers. We previously used a genomics approach to determine novel genes associated with this phenomenon and identified secreted protein acidic and rich in cysteine (SPARC) as a chemosensitizer capable of reversing therapy resistance in colorectal cancer cells by enhancing apoptosis in vitro and tumor regression in vivo. Here, we examined the mechanisms by which SPARC enhances apoptosis in the presence of chemotherapy. We show that SPARC potentiates apoptosis by augmenting the signaling cascade in a caspase-8-dependent manner, because apoptosis can be abolished by caspase 8 small interfering RNA in the presence of SPARC. This occurs independently of death receptor activation and leads to downstream involvement of Bid and subsequent apoptosis. Interestingly, this results from an interaction between SPARC and the N terminus of the procaspase-8 DED-containing domain. These exciting findings provide an initial map of the apoptosis signaling events mediated by SPARC and how this can ultimately result in the reversal of chemotherapy resistance and enhanced tumor regression. This signaling cascade can be exploited therapeutically and may have potential clinical implications for patients with advanced and therapy-refractory cancers.

Received for publication, May 30, 2007 , and in revised form, August 28, 2007.

^* This work was supported by grants from the Canadian Association of Gastroenterology, Canadian Institutes of Health Research, and the Michael Smith Foundation for Health Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables S1 and S2 and supplemental Figs. S1 and S2.

¹ Supported by the Canadian Digestive Health Foundation/Canadian Institutes of Health Research Doctoral Research Award.

² Michael Smith Foundation for Health Research Scholar. To whom correspondence should be addressed: University of British Columbia, Division of Gastroenterology, 2775 Laurel St., Vancouver, BC V5Z 1M9, Canada. E-mail: itai{at}bcgsc.ca.

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